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Methods of treating diseases

Active Publication Date: 2012-08-30
BIOTEMPUS PTY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025]Obtaining a best-fit curve may further comprise imposing a box constraint on at least some of parameters of the model to guide optimisation to biologically realistic regions. In some embodiments, an optimisation algorithm is repeatedly applied using altered levels of degrees of freedom, to allow for differing tolerance to data outliers. A fitted model with the highest log-likelihood may then be chosen for each initial condition for comparison to a fitted model obtained using an alternative nominated initial condition. In this case, close agreement between the chosen fitted models may be taken to improve a confidence in the estimate of the underlying cycle.
[0029]The measurements may also be for two or more different biomarkers which are cycling in the subject, in which case the method comprises determining the preferred timing of administration by reference to two or more sets of measurements. This may provide improved accuracy of estimation of immune system cycling as compared to embodiments which rely on measurements of a single biomarker. Alternatively or additionally, two or more different types of measurements are taken for the same biomarker. For example, daily or sub-daily measurements of an acute phase marker can be taken from a finger prick sample using a hand-held point of care monitoring device coupled with and calibrated by less frequent but more precise measurements obtained by detailed sample examination such as is provided by a professional laboratory.
[0031]In another embodiment, the use of an error distribution is selected to provide robustness against extreme values, for example, the normal, the family of t distributions, the Cauchy, the gamma, the Weibull, and the Johnson S families, preferably the t family.

Problems solved by technology

Despite significant and promising progress, such a response has yet to be fully attained and many immune based therapies have proved disappointing.
Thus, the production of these regulator T cells limits the ability of the immune system to effectively remove cancer cells.
Taking advantage of regulatory T cells has been complicated by an inability to expand and characterize this minor T cell subset, a population of cells reduced even further in autoimmune-prone animals and patients.
For instance, studies have suggested that it may be impossible to reverse ongoing autoimmune diabetes due to the autoreactive T cells becoming resistant to suppression during the active phase of the disease.
Prior efforts to expand regulatory T cells ex vivo have not achieved clinically sufficient expansion, nor demonstrable in vivo efficacy.
The low number of CD4+ CD25+ regulatory T cells, their anergic phenotype and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmune diseases and transplant rejection.
Despite the ground breaking advances described in WO 05 / 040816 and WO 06 / 026821, variations between individuals, variations in sample testing, and the complexity of the disease states make it difficult to manage the data to allow the routine targetting of the desired cell type on the first attempt.

Method used

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  • Methods of treating diseases
  • Methods of treating diseases
  • Methods of treating diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Clinical Trial and Analysis of Data

Methods and Methods

Patients, Treatment and Monitoring

[0242]A pilot clinical study was conducted on 12 patients with metastatic melanoma (median age 61; 4 female; 7 with M1c disease) at The Mayo Clinic, Rochester, Minn., USA headed by Dr Svetomir Markovic. Serial CRP measurements were taken every 2-3 days for 2 weeks. The CRP oscillation cycle was identified by analysis of the raw data without any computer aided modelling, and chemotherapy with temozolomide (200 mg / m2 for 5 days, every 28 days) was initiated. Patients were evaluated for clinical and immune response endpoints every 8 weeks until progression.

Analysis of Immune System Cycling

[0243]In the described embodiment, the model form is:

log(CRPi)=cos(2π×(dayi-offsetperiod))×amplitude+mean+εi

That is, the natural logarithm CRP of a patient on day i is considered a harmonic function where the parameters (period, offset, mean, and amplitude) of the curve are unknown, and are estimated from the data....

example 2

Modelling to Predict Preferred Timing of Administration—Protocol Assessment

Introduction

[0284]The test of the software comprised two main portions: the use of the software on data from real and simulated patients and a simulation study. The overarching goal of the algorithm is to make the prediction as accurate as possible. The inventors can assess its ability to do so in simple, easy-to-grasp cases, as a means of developing intuition about how it will perform in complex cases that are harder to understand.

Simulated Patients

[0285]This example provides a demonstration of the use of the fitting algorithm on simulated patients.

[0286]Random patient were generated as follows:[0287]>p.random

[0288]It will be appreciated that random patients can be generated using any suitable statistical computing environment, such as open-source programming language R and MATLAB.

[0289]The random patient is then processed and reported using the following code ->report(p.random). Note that each simulated pa...

example 3

Simulation Study

Materials and Methods

[0304]The present inventors used the model and fitting algorithm as laid out in Example 1. The goal was to assess the impact upon prediction performance of the number of measures taken, the timeframe over which they were taken, and the pattern of spacing. It is reasonable to expect that the underlying variability of the patients biological signal would also affect the quality of the model fit. Therefore the design for the simulation study comprised the following elements:

[0305]1. Variation in length, including one, one and a half, and two weeks;

[0306]2. Variation in number of measurements, including 8, 10, 15, and 21;

[0307]3. Variation in measurement pattern, including symmetric (S), concentration early and late (B), and concentration late (L); and

[0308]4. Variation in underlying patient variability, including very small (0.25%) and nominal CRP variation (4%) to large (30%).

[0309]The inventors simulated 500 random patients with each of the three ...

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Abstract

The present invention relates to computer-implemented methods and system for analysing a biomarker which cycles in a subject. In some other aspects, the present invention relates to analysing a biomarker which at least initially increases or decreases in amount in a subject following a treatment for a disease. In further aspects, the present invention relates to computer-implemented methods and systems for determining a preferred time to administer a therapy to treat a disease in a subject. The present invention also relates to computer program product to implement the methods. Further, the present invention relates to methods of determining the timing of treating a disease in a subject in which the immune system is cycling.

Description

FIELD OF THE INVENTION[0001]The present invention relates to computer-implemented methods and system for analysing a biomarker which cycles in a subject. In some other aspects, the present invention relates to analysing a biomarker which at least initially increases or decreases in amount in a subject following a treatment for a disease. In further aspects, the present invention relates to computer-implemented methods and systems for determining a preferred time to administer a therapy to treat a disease in a subject. The present invention also relates to computer program product to implement the methods. Further, the present invention relates to methods of determining the timing of treating a disease in a subject in which the immune system is cycling.BACKGROUND OF THE INVENTION[0002]Regulatory T cells[0003]Studies have identified the existence of a naturally occurring population of regulatory / suppressor T cells, which, upon in vitro TCR-mediated stimulation, suppress the proliferat...

Claims

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Application Information

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IPC IPC(8): A61K31/4188G06F19/00A61B5/145A61P35/00G16B5/00G16B40/20G16H20/10
CPCG01N33/564G06F19/34G01N2800/042G01N2800/102G01N2800/104G01N2800/24G01N2800/28G01N2800/2821G01N2800/2828G01N2800/52G01N2800/60G06F19/12A61B5/7267A61B5/41G06F19/24G01N33/57407A61B5/413G16H50/50G16B5/00G16B40/00A61K31/495A61P35/00G16H20/10A61B5/4836G16B40/20G01N33/68G01N2333/4737
Inventor ASHDOWN, MARTIN LEONARDROBINSON, ANDREW
Owner BIOTEMPUS PTY LTD
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